Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor membrane receptors are rapidly down-regulated upon treatment of activated T lymphocytes with various activators of protein kinase C. Loss of binding-capacity was half maximal after 2 min. incubation in 10 ng/ml of phorbol 12-myristate 13-acetate. A similar modulation could be induced with either the calcium ionophore A 23187 or the protein kinase C activator 1-oleyl-2-acetyl glycerol, whereas 1,2-diolein and dibutyryl cAMP were ineffective. Protein kinase C inhibitor H7 antagonizes the phorbol ester-induced TNF receptor modulation. These data suggest an important role of protein kinase C in the control of TNF responsiveness by regulation of TNF binding-capacity possibly via direct phosphorylation of specific receptor proteins.
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PMID:Rapid modulation of tumor necrosis factor membrane receptors by activators of protein kinase C. 302 94

The incubation of human umbilical cord endothelial cell cultures with inflammatory mediators results in the induction of procoagulant activity. As many of these mediators activate protein kinase C, the effect of calmodulin and protein kinase C inhibitors on IL-1, TNF, phorbol ester and LPS stimulated procoagulant activity was determined. Incubation of endothelial cell cultures with these inflammatory agents in the presence of phenothiazine derivatives or other classes of calmodulin and protein kinase C antagonists resulted in a 2-4 fold increase in procoagulant activity compared to parallel stimulated cultures in the absence of antagonists. The augmented response of IL-1 stimulated endothelial cells to these antagonists was actinomycin D sensitive.
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PMID:Augmentation of procoagulant activity in monokine stimulated human endothelial cells by calmodulin/protein kinase C inhibitors. 336 38

Effects of and interactions between tumour necrosis factor alpha (TNF alpha) and bradykinin (BK) on production of interleukin-1 (IL-1 alpha, IL-1 beta) in human gingival fibroblasts were studied. The cytokine TNF alpha induced production of cell-associated IL-1 alpha and IL-1 beta in gingival fibroblasts, with IL-1 beta being most abundant. Addition of BK, in the presence of TNF alpha, for 1 h and 6 h, respectively, synergistically enhanced the TNF alpha induced IL-1 beta production, whereas BK alone did not induce IL-1 production. Similar to BK, two phorbol esters, phorbol 12,13 dibutyrate (PDBu) and phorbol 12-myristate-13-acetate (PMA) which are known to stimulate protein kinase C (PKC), synergistically enhanced the TNF alpha induced IL-1 beta production in the gingival fibroblasts. On the contrary, a phorbol ester which does not activate protein kinase C, 13-phorbolacetate (13-PA), did not potentiate the TNF alpha induced IL-1 beta production. Similar to BK, the phorbol esters (PMA, PDBu, 13-PA) alone did not induce IL-1 beta production in the gingival fibroblasts. The results indicate that TNF alpha induces production of cell-associated IL-1 in gingival fibroblasts, which can be upregulated by a PKC dependent pathway.
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PMID:Effects and interactions of tumour necrosis factor alpha and bradykinin on interleukin-1 production in gingival fibroblasts. 747 1

The procoagulant response of endothelium to pathophysiological agents such as tumour necrosis factor alpha (TNF alpha) and phorbol myristate acetate (PMA) alters the expression of proteins such as tissue factor. The modulation of such procoagulant activity (PCA) by the polyunsaturated fatty acid arachidonic acid (20:4,n-6) and its 15-hydroperoxy (15-HPETE) and 15-hydroxy (15-HETE) metabolites was examined since this may have important implications in cardiovascular disease and atherosclerosis. Treatment of human umbilical vein endothelial cells (HUVEC) for 30 min with 20:4, 15-HPETE or 15-HETE before induction of PCA with TNF alpha (100 U) or PMA (10(-7) M) caused a significant inhibition of PCA. This inhibition was seen at 2-5 microM fatty acids. Dose response curves with TNF alpha indicated that the inhibition was greatest at higher concentrations of TNF alpha (> or = 250U TNF alpha/ml). The mode of administration of the fatty acid was not critical as fatty acids presented as DPC-fatty acid micelles or solubilised in ethanol gave similar inhibitions of PCA. 20:4, 15-HPETE or 15-HETE did not alter the binding of I125-labelled TNF alpha to its surface receptors on HUVEC, suggesting that the effect of these fatty acids was not mediated by events at the cell surface receptor level. In support of this, these fatty acids were found to inhibit PCA induced by PMA which bypasses cell surface receptors to activate protein kinase C directly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory effects of arachidonic acid (20:4,n-6) and its monohydroperoxy- and hydroxy-metabolites on procoagulant activity in endothelial cells. 748 27

TNF stimulated transcription and secretion of the metalloproteinases collagenase and stromelysin in porcine articular chondrocytes. TNF induced metalloproteinase transcription could be inhibited with either protein kinase inhibitors (H7 or staurosporine) or by raising intracellular cAMP levels. HA1004, a protein kinase inhibitor structurally related to H7 but with a higher Ki for protein kinase C had no effect on TNF induced message levels. TNF treatment of chondrocytes did not induce membrane associated PKC or increase intracellular cAMP levels. Our results are consistent with the involvement of a staurosporine and H7 sensitive protein kinase distinct from PKC in TNF signal transduction in chondrocytes.
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PMID:Protein kinase regulation of tumor necrosis factor alpha stimulated collagenase and stromelysin message levels in chondrocytes. 750 65

The fate of E-selectin expressed on TNF-activated monolayers of HUVEC was investigated by confocal laser scanning microscopy. Cytokine-activated endothelial cells internalized mAb to E-selectin in a very rapid, energy-dependent fashion. By contrast, mAb against ICAM-1 and VCAM-1 remained surface bound. The E-selectin mAb was recovered in intracellular compartments with a tubular morphology, some of which appeared to be interconnected. Cathepsin B, a ubiquitously expressed lysosomal protease, was found to co-localize in these structures. Functional specificity of E-selectin-internalization was observed upon addition of the fluorescent SLex-oligosaccharide to the activated HUVEC monolayers. Uptake into the same E-selectin-positive compartments was observed, whereas the control oligosaccharide Lex was not internalized at all. The process of internalization was found to be unaffected by most inhibitors of protein kinase C, cAMP-dependent PKA, or protein tyrosine kinase activity. Whereas cytochalasin B preincubation of HUVEC failed to inhibit the internalization process, colchicine and vinblastine, reagents that interfere with the metabolism of tubulin, prevented the formation of the elongated structures in which E-selectin would normally be internalized. Concomitantly, the expression of E-selectin at the cell surface was significantly increased.
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PMID:Cytokine-activated endothelial cells internalize E-selectin into a lysosomal compartment of vesiculotubular shape. A tubulin-driven process. 751 27

Vascular smooth muscle cells (SMC) respond by relaxation to nitric oxide (NO) released from the endothelium which expresses a constitutive, Ca(2+)-dependent NO synthase (cNOS). SMC can, however, produce NO themselves upon stimulation by proinflammatory cytokines which induce expression of an inducible, Ca(2+)-independent NO synthase (iNOS). Protein kinase C represents another important second messenger system involved in the regulation of SMC contraction. We have investigated iNOS expression and NO synthesis in rat vascular SMC treated with the cytokines, IFN gamma and TNF alpha, in the presence or absence of the activator of protein kinase C, beta-phorbol-12-myristate 13-acetate (PMA). Treatment with PMA did not induce any significant accumulation of nitrite, a major stable metabolite of NO, in SMC. When added simultaneously with the cytokines, PMA significantly reduced nitrite accumulation induced by cytokine stimulation in a dose-dependent fashion. This inhibitory effect was mediated by activation of PKC since calphostin C, a specific PKC inhibitor, abolished the PMA effect. Further analysis of iNOS mRNA with a rat iNOS cDNA probe demonstrated that addition of PMA reduced expression of SMC iNOS mRNA, indicating that the antagonism in induction of NO synthesis between PMA and the proinflammatory cytokines acts on the transcriptional level. The inhibitory effect of PMA may be mediated via induction of a suppressor of iNOS expression, since pretreatment with PMA reduced NO production after subsequent treatment with cytokines. These observations suggest that activation of the PKC pathway is involved in a negative regulation of iNOS gene expression and this is compatible with the observation that vascular SMC contraction can be induced by PKC activation.
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PMID:Protein kinase C activation inhibits cytokine-induced nitric oxide synthesis in vascular smooth muscle cells. 752 Feb 82

We have previously found that lipoprotein lipase (LPL) induces tumor necrosis factor alpha (TNF alpha) mRNA expression and TNF alpha protein production in the ANA-1 macrophage cell line and in resident murine macrophages. The present study was designed to elucidate the intracellular signalling pathways involved in the LPL-induced TNF alpha gene expression. Treatment of macrophages with two protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H7) and calphostin C, suppressed LPL-induced TNF alpha mRNA expression and protein production. In contrast, no inhibition of the TNF alpha mRNA expression occurred when macrophages were exposed to an inhibitor of calmodulin-dependent kinase N-(6-amino-hexyl)-5-chloro-1-naphthalene-sulfonamide hydrochloride (W7). Overnight treatment of ANA-1 cells with 100 ng/ml 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) caused the suppression of both PKC activity and LPL-induced TNF alpha mRNA expression. We have also found that LPL treatment increased PKC activity in macrophages and induced a translocation of this enzyme from the cytosol to the membrane. Finally, we have demonstrated that H7 inhibited the enhancement of nuclear protein binding to the NFkB consensus sequence in the promoter of the TNF alpha gene that we observed in LPL-treated macrophages. Moreover, the treatment of macrophages with H7 abolished the stabilization of TNF alpha mRNA in response to LPL. Overall these data demonstrate that LPL induces TNF alpha mRNA expression in a PKC-dependent manner and that the PKC effect involves transcriptional events as well as posttranscriptional modifications.
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PMID:Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase requires protein kinase C activation. 752 52

Infections with verocytotoxin (VT) producing Escherichia coli have been strongly implicated in the epidemic form of hemolytic uremic syndrome (HUS). Endothelial damage plays a central role in the pathogenesis of HUS. In vitro studies have shown that VT can damage endothelial cells after interaction with its cellular receptor globotriaosylceramide (GbOse3cer). Cytokines, such as tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) can potentiate the toxic effect of VT by inducing a protein-synthesis dependent increase in VT receptors on endothelial cells. In this study, the mechanisms underlying the increase in endothelial VT receptors induced by TNF alpha were studied in more detail. To investigate which proteins were involved in this induction, endothelial cells were incubated with and without TNF alpha in the presence of 14C-galactose or 14C-glucose. Thin-layer chromatography (TLC) analysis of the glycolipid extracts of these cells demonstrated a markedly enhanced incorporation of 14C-galactose in GbOse3cer and other galactose-containing glycolipids, suggesting that TNF alpha enhanced galactosyl-transferase activity. To examine the role of the two recently cloned TNF-receptors (TNFR-p75 and TNFR-p55) in the TNF alpha-induced increase in GbOse3cer in human endothelial cells, cells were incubated with TNF alpha, the TNFR-p55 selective R32W-S86T-TNF alpha-mutant, or the TNFR-p75 selective D143N-A145R-TNF alpha-mutant. The effect of TNF alpha activation, determined by binding-experiments with 125I-VT-1, could be largely, but not completely mimicked by R32W-S86T-TNF alpha. Although incubation of cells with D143N-A145R-TNF alpha did not show an increase in VT-1 binding, the monoclonal antibody utr-1, which prevents binding to TNFR-p75, decreased the TNF alpha-induced VT-1 binding. Activation of protein kinase C (PKC) by phorbol ester increases the expression of VT-1 receptors; this effect was prevented by the PKC inhibitor Ro31-8220 and by homologous desensitization by pretreatment with phorbol ester. In contrast, the presence of the protein kinase inhibitor Ro31-8220 or desensitization of PKC activity reduced the TNF alpha-induced increase in VT-1 receptors maximally by 50% and 24%, respectively. Comparable reductions in overall protein synthesis and the synthesis of E-selectin and plasminogen activator inhibitor-1 (PAI-1) were observed. This suggests an effect on general protein synthesis rather than a specific effect of PKC in the signal transduction pathway, by which TNF alpha induces VT-1 receptors. Our results indicate that TNF alpha can increase the VT-1 receptors on endothelial cells by inducing galactosyl-transferase activity, that this action of TNF alpha mainly occurs via the TNFR-p55; and that PKC activation increases expression of VT-1 receptors by a separate mechanism that acts additively to the TNF alpha-induced increase in VT-1 receptors.
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PMID:Tumor necrosis factor alpha induces endothelial galactosyl transferase activity and verocytotoxin receptors. Role of specific tumor necrosis factor receptors and protein kinase C. 753 May 4

We have previously described a family of benzamide derivatives that showed antiinflammatory activity in vivo on carragenin-induced paw edema and experimental cerebral edema. Those compounds inhibited eicosanoids production from activated macrophages (M phi) without inhibiting cyclooxygenase. To further investigate their antiinflammatory activity and compare it to that of classical cyclooxygenase inhibitors, we analyzed their effect on the production of a major proinflammatory cytokine, tumor necrosis factor (TNF-alpha), by in vitro-activated peritoneal macrophages. We show that, in marked contrast with ibuprofen, flurbiprofen and indomethacin which all significantly enhanced TNF production, the two benzamide derivatives tested, JM34 and JM42, significantly inhibited TNF-alpha production by zymosan or lipopolysaccharide-activated M phi. Those compounds did not interfere with the calcium-dependent pathway because they did not affect TNF production of either mice peritoneal M phi or human T cell clones induced by the calcium ionophore A23187 alone. More likely, these benzamide derivatives acted mainly at the level of the protein kinase C (PKC) pathway because: 1) After treatment of M phi with PKC inhibitors which significantly inhibited TNF production, our compounds showed no additional inhibition. 2) Our compounds significantly inhibited TNF production of M phi stimulated with the phorbol ester phorbol di-butyrate alone or in combination with A23187. 3) After depletion of PKC by prolonged phorbol di-butyrate treatment of M phi, inhibition of TNF production by our compounds was markedly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New antiinflammatory compounds that inhibit tumor necrosis factor production: probable interaction with protein kinase C activation. 756 46


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